Aggression is a near universal behavior. Among social animals, appropriately balanced aggressive behavior gives rise to a stable social organization by creating and maintaining dominance hierarchies. Inappropriate aggression has detrimental consequences for a society. Sociopathic and violent behaviors place a significant socioeconomic burden on human societies. Aggression can result from traumatic brain injury, neurodegenerative diseases, and as a comorbid condition of drug or alcohol abuse. Aggressive behavior is a typical quantitative trait, with natural variation attributable to segregating variants at multiple interacting loci, th effects of which are sensitive to the environment. Despite substantial evidence for genetic predisposition to aggressive behavior in humans, only a handful of candidate genes associated with variation in aggression have been identified in human populations. Drosophila provides an excellent model for systems genetics analysis of naturally occurring variation in aggression. We generated the Drosophila Genetic Reference Population (DGRP), which consists of 192 fully sequenced inbred strains derived from the Raleigh, USA population as a public resource for genome-wide association (GWA) analysis of quantitative traits. This population harbors substantial genetic variation for aggressive behavior and provides an essential resource for this application. Our ultimate goal is to obtain a complete understanding of the genetic architecture of aggressive behavior and biological effects of natural variants on transcriptional genetic networks. The specific aims of this proposal are (1) to use the power of Drosophila genetics and genomics to map putative causal alleles associated with variation in aggression with high resolution and develop a statistical genetic model to predict individual aggressive behavior; (2) to derive causal transcriptional co-expression networks affecting aggressive behavior, placing novel loci identified by genetic mapping in appropriate biological context; and (3) to use mutations and RNAi to functionally test effects on aggressive behavior of genes implicated by the statistical analyses of natural variation and architecture of transcriptional networks, and to use the recently developed system for integrating transgenes in the same genomic location to perform tests for causal effects of natural alleles on aggressive behavior. Because aggression is a universal behavior and many genes in Drosophila have human orthologues, general insights derived from our proposed studies will have translational implications for human genetic studies on aggression; moreover, insights derived from systems genetic studies on aggression, will have a broad impact on our general understanding of quantitative traits, including the genetics of human behavioral disorders. PUBLIC HEALTH RELEVANCE: Increased levels of aggression occur in alcoholics, Alzheimer's Disease patients, and individuals suffering from behavioral disorders, such as borderline personality disorder and intermittent explosive disorder. The social and economic costs to our society that result from violent behavior, and efforts to control it, are enormous. This study utilizes a new genetic resource, full sequenced Drosophila lines, and state-of-the-art gene expression, statistical and genetic analyses to map molecular variants affecting aggression, and derive gene expression networks causally associated with aggressive behavior. Given the evolutionary conservation of function for fundamental traits, such as aggression, genes and pathways discovered in model organisms can be incorporated as candidate genes in human linkage and association studies.